Summary of Work: Apoptosis is a form of programmed cell death that occurs under numerous developmental and physiological conditions in order to eliminate unwanted or damaged cells from organisms. The activation of apoptosis has important implications in a variety of human diseases including, cancer, AIDS, autoimmune diseases and in response to environmental toxins. 1) We are studying the catabolic effectors that carry out the apoptotic process and degrade DNA, RNA, and protein during programmed death or apoptosis. We have identified and characterized one nuclease, cyclophilin and several other candidate nucleases which are now being studied. We have also shown that 28S ribosomal RNA is specifically degraded during apoptosis. This appears to be activated via the modification of the ribosomal P3 protein. 2) Apoptosis is activated by many different signals operating through a diverse array of signal transduction pathways. Thus we have sought to define common activation pathways for apoptosis that are independent of both the apoptotic signal and cell type. We have shown that cell shrinkage and K+ efflux must occur for both caspase activation and DNA fragmentation. Current efforts are directed towards elucidating the ion channels necessary for K+ efflux. 3) A third effort has been in the area of genetic approaches to define components of the cell death pathway. Somatic cell fusion studies shown that the apoptotic phenotype is recessive. Using a rescue cloning approach we have recently cloned a novel inhibitor of apoptosis. 4) Finally, we are identifying the mechanisms of transcriptional activation of apoptosis by glucocorticorids with particular emphasis on kinases/phosphatases whose activity can affect protein phosphorylation and the activity of death signalling enzymes.